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OK. Hello everyone and thank you for coming to our Oncology Society teaching for Oncology. Um I feel a little bit it's making a bit louder. So sorry about that. Is it just because I'm recording it? Yeah, I know it says that um it's progress test based teaching, but I do have a bit of preclinical things in this as well just because I feel that while you, you will be preparing for the MLA and for future knowledge in oncology, this would be useful for you to know there are some details in here that you wouldn't be expected to memorize. But I felt it would be useful to include when going through an overview of aspects of oncology before we head over to the clinical side. So hopefully that won't take too long. Um If we can go to that side, please. So here we have um the topics that we'll be covering today and it won't be every single cancer. Unfortunately, because we won't have time for that. We'll try to cover endocrine and the main gyne cancers as well as gi cancers, a few brain malignancies as well as he malignancies, which do tend to take up a big part of the oncology portion of PT S and MLA next slide, please. Um So this is question one, you are attending a lecture on the cell cycle to understand principles of chemotherapy. After which phase is an important checkpoint before DNA synthesis. So, um if you want to, you can put your answers in the chat or if you can privately message it to me if you feel more comfortable. OK. Um If we could go to the next slide for the answer, the answer is G one and I'll explain more when we talk about the cell cycle. So if we can go to the next slide, please, um I thought it would be good to overview the basics of the cell cycle. Again, you won't have to memorize the Cyclin D or CDK because S two is over. But it is important to remember the general aspects of the cell cycle to understand the components of chemotherapy, especially when you're memorizing their mechanisms and their effects for certain cancers, which will be useful for MLA. So basics of cell cycle is the process by which the cell grows, replicates the DNA and divides into its two daughter cells. And the distinct changes are regulated by cyclins and cyclin dependent kinases. So as you know, they're the regulatory proteins and enzymes that control the cell cycle progression and they tend to fluctuate throughout the cycle. So they increase, increase at specific phases and degrade afterwards. When it wants to move the cell to the next part of the cycle, the enzymes especially are very important to phosphorylate target proteins to drive the transitions of the cell cycle. So in the cell cycle, we have roughly the interface which covers gap one or G one S where DNA replication occurs and gap two phase. And then we have the M phase which is mitosis and that's involving the division of the cell's nucleus and its contents as well as cytokinesis. Um The importance of the checkpoints is to understand the mechanisms behind cancer cell proliferation and why certain chemotherapies tend to target, target certain parts of these checkpoints depending on the genetic mutation implicated in the cancer. Um And that especially becomes important for things like P 53 mutations or BRCA mutations. So the G one and S checkpoint or the restriction point is especially important to make sure the cell is ready for DNA replication. And it's regulated by P 53 the RB renal blastoma protein and Cyclin D. And it's relevant because mutations in P 53 which is a tumor suppressor is going to prevent the detection of DNA damage, which allows damaged cells to replicate. And then the loss of RB function would lead to unchecked progression of these damaged cells into the S phase. We technically also have an S phase checkpoint. It's not really put over here. But what happens is that um there's monitoring of the DNA replication for errors. And that's when things like BRCA one and BRCA two come in because what they do is that um they're supposed to aid the repair of damaged DNA and when that is impaired, it increases the risk of malignancies, especially of the breast and the ovaries. Um The other two are ATM and Atr Ataxic inject, which are quite specific conditions and they're not relevant to cancers that you need to know about G two and M checkpoint is really important to make sure that the DNA is fully replicated and, and um damaged before mitosis. And again, that's where P 53 and C HK one and two come in. Um They're important because a damage or dysfunction to those enzymes and proteins will lead to genomic instability and genomic instability is often a cause of cancers like colorectal cancer and ovarian cancer, which we'll talk more about. Um next side, please. OK. Um This is a bit more difficult. You are in oncology clinic explaining to a patient the role of a drug used in their cancer, which of the following correctly matches a class of chemotherapeutic drugs with its primary mechanism of action. I'll also answer your question while you're OK. So the answer for that is to um I'll type up the answer to the question in the chat as well after I've answered this one, if that's OK. So if we could go on to the left side, um roughly the mechanisms of chemotherapeutic drugs are summarized here and it looks a bit complicated, but in reality, you won't be expected to memorize the exact mechanism of every one of these. Um This is just important to remember that they can target different aspects of DNA replication and cell cycle progression. Um And the most important takeaway from this whole thing is that most um anticancer drugs will target the S phase and the M phase. So the part where DNA synthesis is taking place and the part where mitosis is happening, especially microtubule, uh modifiers like taxanes, which you'll see in a lot of cancers, including um the treatment of breast cancer and ovarian cancer. Um anti metabolites also have many different causes, but their main function is to impair nucleotide synthesis, folic acid regeneration and DNA replication as well. Um So if we go on to the next slide, this table kind of summarizes the examples of the different classes of the drugs and what their function is, we have top isomerase inhibitors which tend to uh prevent DNA unwinding and replication, which is the function of the top isomerase in the cell. We have the microtubule inhibitors as it said. So they tend to impair the mitotic spindle formation during metaphase and anaphase. Um Although they act in different ways, um we have the antitumor antibiotics which aren't um they can be used for specific cancers, but you won't be asked on PT um what cancers is this used for, you might be more likely to be asked. Um For example, um what might be the function of an antimetabolite or what might be the mechanism for an alkylating agent? And it might not even be necessary to remember these specific names. Um But it again, it is good revision for Emily because the point of PT is to continuously prepare you for the Emily you'll take at the end of medical school with regards to your immune checkpoint inhibitors. Um This is an interesting point because I believe in the um question that I wrote that I put immune checkpoint inhibitors and then I said um repairing cell cycle, which was the incorrect answer in that case. Um And the reason being, I think there's a lot of infusion with the fact that it says checkpoint inhibitors, there's a difference between um cell cycle checkpoint inhibitors and immune checkpoint inhibitors. So if we go back to your two, we have PDL one ligands that are the, please don't kill me. Signal for cytotoxic T cells to recognize and to not kill native cells. And when can cancer cells start to mimic those cells, they don't get killed by those cells. So the point of immune checkpoint inhibitors are to stop or block the PD L1 receptor and therefore make it easier for those T cells to come and kill them. So that's an external process that's mediated by the immune response of the body. The checkpoints in the cell.